Ticagrelor is a novel, selective micromolecule anti-clotting drug developed by AstraZeneca. It is also the first reversibly-binding oral P2Y12 adenosine diphosphate receptor antagonist, having significantly inhibitory effect for ADP-induced platelet aggregation. It can effectively improve the symptoms of patients with acute coronary artery disease. This drug was approved by EMEA and US FDA to sell on the markets in EU countries and the United States in 2010 and 2011 respectively. Its imported preparation Ticagrelor tablets have been approved in the markets in china by China Food and Drug Administration (CFDA).
Ticagrelor chemical name: (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(prop-mercapto-)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol.

The synthesis route and preparation method of Ticagrelor have been reported. By investigating the disclosed synthesis route and preparation method, it is found that although the routes are different, most processes adopt the different chemical reactions, different reaction orders, and different linking modes of following three intermediates A, B and C to prepare Ticagrelor.

The synthesis route of patents WO9703084, WO99/05142, WO2000/34283 and WO2012/138981 is described as follows:

The difference between the synthesis method in patent WO2001/36421, WO2001/36438 WO2011/017108 and above route is first introduction of 2-alcohol functional group in five-membered ring and reduction of nitro in pyrimidine ring to amino. In addition, in the patent WO2012/139455 and CN102675321, considering the possible side reaction in subsequent reactions of 2-alcohol functional group, hydroxyl group is firstly protected, and then amine substitution reaction is performed, and finally to generate Ticagrelor by deprotection.

In the Patent WO2012/172426, methyl acetate functional group is retained in the five-membered ring, and after completing linking of three intermediates, the ester group is reduced to alcohol.

The Patent WO13/037942 WO12/085665 and EP2570405 reported another method of condensing the intermediate B and the pyrimidine ring. Through the protection of amino on cyclopropanamine, the selectivity of the condensation reaction increases.
Patent CN102311437 proposed another idea for the method of linking five-membered ring (Intermediate C) with the pyrimidine ring and triazole (Intermediate A). It achieves coupling through the hydroxyl group on the five-membered ring and nitrogen atoms on triazole with the actions of triphenylphosphine and diethyl azodicarboxylate. However, due to the direction of triazole ring, the coupling position is difficult to control.

In addition, patents CN103130726, CN102250097, WO2011/101740, US2011/071290, WO2010/03224, WO2007093368 and WO2005/095358 studied the method for preparing Ticagrelor pyrimidine ring (Intermediate A). Patents WO2012/001531, WO2011/132083, CN1431992, CN1334816, CN101495444, CN101495442, CN102796007 and CN102249929 studied the method for preparing Ticagrelor three-membered ring (Intermediate B); and patents WO2010/030224, US2010/069408 and CN102659815 focused on the synthesis and preparation method of Ticagrelor five-membered ring (Intermediate C).
In summary, up to now, all published literatures on the preparation of Ticagrelor focused on the preparation, protection, linking and reactions of three important intermediates (intermediates A, B and C). To seek new intermediates and synthetic routes to facilitate the preparation of Ticagrelor in a simple, economic and environmental way is essential to the economic and technological development of the API.